2019-68-3

Usage

Synthesis Reference(s)

Journal of Medicinal Chemistry, 46, p. 2494, 2003 DOI: 10.1021/jm020546rTetrahedron Letters, 21, p. 1219, 1980 DOI: 10.1016/S0040-4039(00)71375-X

InChI:InChI=1/C9H11NO2/c1-9(12,8(10)11)7-5-3-2-4-6-7/h2-6,12H,1H3,(H2,10,11)

Upstream product

• 20102-12-9 2-hydroxy-2-phenylpropionitrile 
• 127462-20-8 2-phenyl-2-trimethylsilyloxypropanenitrile 
• 98-86-2 acetophenone 

Downstream Products

• 20907-29-3 2-hydroxy-2-phenyl-pentan-3-one 
• 5623-26-7 α-methylbenzoin 
• 515-30-0 2-phenyllactic acid 
• 1565-75-9 2-phenyl-2-butanol 
• 98-86-2 acetophenone 
• 101716-26-1 1-phenyl-1,2,3,4-tetrahydro-naphthalene-1r,4t-dicarbonyl chloride 
• 860572-88-9 2,3-dichloro-2-phenyl-propionyl chloride 
• 2019-66-1 C₁₁H₁₃NO₃ 

Relevant academic research and scientific papers

Hydration of Cyanohydrins by Highly Active Cationic Pt Catalysts: Mechanism and Scope

Cyanohydrins (α-hydroxy nitriles) are a special type of nitriles that readily decompose into hydrogen cyanide (HCN) and the corresponding carbonyl compounds. Hydration of cyanohydrins that are readily available through cyanation of aldehydes and ketones provides the most straightforward route to valuable α-hydroxyamides. However, due to low stability of cyanohydrins and deactivation of the catalysts by the released HCN, catalytic direct hydration of cyanohydrins still remains largely unsolved. As a general trend, cyanohydrins containing bulkier substituents, such as α,α-diaryl cyanohydrins, degrade more quickly and thus are more difficult to be hydrated. Here, we report development of cationic platinum catalysts that exhibit high reactivity for hydration of various cyanohydrins. Detailed mechanistic investigations for hydration of nitriles by (PμP)Pt(PR2OH)X(OTf) reveal a catalytic cycle involving the formation of a five-membered metallacyclic intermediate and subsequent hydrolysis via attacking on the phosphorus of the secondary phosphine oxide (PR2OH) ligand by H2O. We discovered that Pt catalyst A bearing the electron-rich, appropriately small-bite-angle bisphosphine ligand provides super reactivity for hydration of cyanohydrins. The hydration reactions catalyzed by A proceed at ambient temperatures and occur with a wide variety of cyanohydrins, including the most difficult α,α-diaryl cyanohydrins, with good turnover numbers.

Catalytic Transfer Hydration of Cyanohydrins to α-Hydroxyamides

We report the palladium(II)-catalyzed transfer hydration of cyanohydrins to α-hydroxyamides by using carboxamides as water donors. This method enables selective hydration of various aldehyde- and ketone-derived cyanohydrins to afford α-mono- and α,α-disubstituted-α-hydroxyamides, respectively, under mild conditions (50 °C, 10 min). The direct conversion of fenofibrate, a drug bearing a benzophenone moiety, into a functionalized α,α-diaryl-α-hydroxyamide was achieved by means of a hydrocyanation-transfer hydration sequence. Preliminary kinetic studies and the synthesis of a site-specifically 18O-labeled α-hydroxyamide demonstrated the carbonyl oxygen transfer from the carboxamide reagent into the α-hydroxyamide product.

Design, synthesis and evaluation of novel hydroxyamides as orally available anticonvulsants

Themisone, also known as Atrolactamide, was found, in the 1950s, to be a very potent anticonvulsant. It was hypothesized that the -CF3 substitution would maintain the anticonvulsant activity. Anticonvulsant testing of our novel compounds by the

Synthesis and structure-activity relationship studies for hydantoins and analogues as voltage-gated sodium channel ligands

We previously developed a preliminary 3-D QSAR model for the binding of 14 hydantoins to the neuronal voltage-gated sodium channel; this model was successful in designing an effective non-hydantoin ligand. To further understand structural features that result in optimum binding, here we synthesized a variety of compound classes and evaluated their binding affinities to the neuronal voltage-gated sodium channel using the [3H]-batrachotoxinin A 20-α-benzoate ([3H]BTX-B) binding assay. In order to understand the importance of the hydantoin ring for good sodium channel binding, related non-hydantoins such as hydroxy amides, oxazolidinediones, hydroxy acids, and amino acids were included. Two major conclusions were drawn: (1) The hydantoin ring is not critical for compounds with long alkyl side chains, but it is important for compounds with shorter side chains. (2) Relative to Khodorov's pharmacophore, which contains two hydrophobic regions, a third hydrophobic region may enhance binding to provide nanomolar inhibitors.

Design, synthesis, and evaluation of analogues of 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide as orally available general anesthetics

We have recently discovered a novel class of compounds that have oral general anesthetic activity, potent anticonvulsant activity, and minimal hemodynamic effects. The 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide (1) demonstrated potent ability to reduce the minimum alveolar concentration (MAC) of isoflurane, with no effects on heart rate or blood pressure at therapeutic concentrations. Analogue 1 also had potent oral anticonvulsant activity against maximal electroshock (MES) and subcutaneous metrazol (scMET) models with a therapeutic index of 10 for MES activity. In this study, we further synthesized nine new racemic analogues and evaluated these compounds for effects on isoflurane MAC reduction and blood pressure. Preliminary data demonstrate potent reduction in the isoflurane MAC for two new compounds. Current mechanistic studies were unrevealing for effects on voltage-gated ion channels as a putative mechanism. Liposomal partitioning studies using 19F NMR reveal that the aromatic region partitions into the core of the lipid. This partitioning correlated with general anesthetic activity of this class of compounds. Further, compound 1 was used at a concentration of 1 mM and slightly enhanced GABAA current in hippocampal neurons at 10 μM. Altogether, 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide exhibited excellent oral general anesthetic activity and appears devoid of significant side effects (i.e., alterations in blood pressure or heart rate).

SYNTHESIS OF α-HYDROXIAMIDES VIA THE CYANOSILYLATION OF AROMATIC KETONES

The trimethylsilyl ethers of the cyanohydrins of aryl-alkyl ketones and diaryl ketones afforded the corresponding α-hydroxyamides upon hydrolysis with HCl or HNO3/HCO2H.The method is advantageous for ketones do not readily undergo addition of HCN.